CBD & PARKINSON’S DISEASE

CBD AND PARKINSON’S DISEASE

The endocannabinoid system and digestive imbalance play major roles in Parkinson’s disease. Research on CBD, THC, and THCV has demonstrated that cannabis medicine may help to manage PD symptoms.
BY NISHI WHITELY ON JULY 12, 2017
Highlights:
  • The endocannabinoid system plays a major role in Parkinson’s Disease (PD).
  • PD is associated with impairment of motor control after the loss of 60-80% of dopamine-producing neurons in a critical brain region.
  • Digestive imbalance may play a role in the advancement of PD & the severity of symptoms.
  • Cannabinoids have neuroprotectant, anti-oxidant and anti-inflammatory properties which can be beneficial for managing PD.
  • Various combinations of CBD, THC, and THCV may provide relief for Parkinson’s symptoms.
How cannabinoid therpay may help Parkinson's disease
Photo credit: pixabay

Scientists at the University of Louisville School of Medicine in Kentucky have identified a previously unknown molecular target of cannabidiol (CBD), which may have significant therapeutic implications for Parkinson’s Disease (PD).

A poster by Zhao-Hui Song and Alyssa S. Laun at the 2017 meeting of the International Cannabinoid Research Society in Montreal disclosed that CBD activates a G-coupled protein receptor called “GPR6” that is highly expressed in the basal ganglia region of the brain. GPR6 is considered an “orphan receptor” because researchers have yet to find the primary endogenous compound that binds to this receptor.(1)

It has been shown that a depletion of GPR6causes an increase of dopamine, a critical neurotransmitter, in the brain. This finding suggests GPR6 could have a role in the treatment of Parkinson’s, a chronic, neurodegenerative disease that entails the progressive loss of dopaminergic (dopamine-producing) neurons and consequent impairment of motor control. By acting as an “inverse agonist” at the GPR6 receptor, CBD boosts dopamine levels in preclinical studies.

Parkinson’s affects an estimated 10 million people worldwide, including one million Americans. It is the second most common neurological disorder (after Alzheimer’s Disease). Over 96 percent of those diagnosed with PD are over 50 years old with men being one-and-a-half times more likely to have PD than women. Uncontrolled PD significantly reduces the patient’s quality of life and can render a person unable to care for themselves, trapped in a body they cannot control.

Dopamine depletion

Parkinson’s Disease is most associated with compromised motor function after the loss of 60-80% of dopamine-producing neurons. As dopaminergic neurons become damaged or die and the brain is less able to produce adequate amounts of dopamine, patients may experience any one or combination of these classic PD motor symptoms: tremor of the hands, arms, legs or jaw; muscle rigidity or stiffness of the limbs and trunk; slowness of movement (bradykinesia); and /or impaired balance and coordination (postural instability).

Additional symptoms include decreased facial expressions, dementia or confusion, fatigue, sleep disturbances, depression, constipation, cognitive changes, fear, anxiety, and urinary problems. Pesticide exposure and traumatic brain injury are linked to increased risk for PD. Paraquat, an herbicide sprayed by the DEA in anti-marijuana defoliant operations in the United States and other countries, resembles a toxicant MPTP [methyl-phenyl-tetrahydropyridien], which is used to simulate animal models of Parkinson’s for research purposes.(2)

Within the PD brain there are an inordinate number of Lewy bodies – intracellular aggregates of difficult to break down protein clusters – that cause dysfunction and demise of neurons.(3) This pathological process results in difficulties with thinking, movement, mood and behavior. The excessive presence of Lewy bodies, coupled with the deterioration of dopaminergic neurons, are considered to be hallmarks of Parkinson’s. But mounting evidence suggests that these aberrations are actually advanced-stage manifestations of a slowly evolving pathology.

It appears that non-motor symptoms occur for years before the disease progresses to the brain, and that PDis actually a multi-system disorder, not just a neurological ailment, which develops over a long period of time. According to the National Parkinson’s Foundation, motor symptoms of PD only begin to manifest when most of the brain’s dopamine-producing cells are already damaged.

Patients whose PD is diagnosed at an early stage have a better chance of slowing disease progression. The most common approach to treating PD is with oral intake of L-dopa, the chemical precursor to dopamine. But in some patients, long-term use of L-dopa will exacerbate PD symptoms. Unfortunately, there is no cure – yet.

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Gut-brain axis

What causes Parkinson’s? One theory that is gaining favor among medical scientists traces the earliest signs of PD to the enteric nervous system (the gut), the medulla (the brainstem), and the olfactory bulb in the brain, which controls one’s sense of smell. New research shows that the quality of bacteria in the gut – the microbiome – is strongly implicated in the advancement of Parkinson’s, the severity of symptoms, and related mitochondrial dysfunction.

Defined as “the collection of all the microorganisms living in association with the human body,” the microbiome consists of “a variety of microorganisms including eukaryotes, archaea, bacteria and viruses.” Bacteria, both good and bad, influence mood, gut motility, and brain health. There is a strong connection between the microbiome and the endocannabinoid system: Gut microbiota modulate intestinal endocannabinoid tone, and endocannabinoid signaling mediates communication between the central and the enteric nervous systems, which comprise the gut-brain axis.

Viewed as “the second brain,” the enteric nervous system consists of a mesh-like web of neurons that covers the lining of the digestive tract – from mouth to anus and everything in between. The enteric nervous system generates neurotransmitters and nutrients, sends signals to the brain, and regulates gastrointestinal activity. It also plays a major role in inflammation.

The mix of microorganisms that inhabit the gut and the integrity of the gut lining are fundamental to overall health and the ability of the gut-brain axis to function properly. If the lining of the gut is weak or unhealthy, it becomes more permeable and allows things to get into the blood supply that should not be there, negatively impacting the immune system. This is referred to as “leaky gut.” Factor in an overgrowth of harmful bacteria and a paucity of beneficial bacteria and you have a recipe for a health disaster.

The importance of a beneficial bacteria in the gut and a well-balanced microbiome cannot be overstated. Bacterial overgrowth in the small intestine, for example, has been associated with worsening PD motor function. In a 2017 article in the European Journal of Pharmacology, titled “The gut-brain axis in Parkinson’s disease: Possibilities for food-based therapies,” Peres-Pardo et al examine the interplay between gut dysbiosis and Parkinson’s. The authors note that “PD pathogenesis may be caused or exacerbated by dysbiotic microbiota-induced inflammatory responses … in the intestine and the brain.”(4)

Mitochondria, microbiota and marijuana

The microbiome also plays an important role in the health of our mitochondria, which are present in every cell in the brain and body (except red blood cells). Mitochondria function not only as the cell’s power plant; they also are involved in regulating cell repair and cell death. Dysfunction of the mitochondria, resulting in high levels of oxidative stress, is intrinsic to PD neurodegeneration. Microbes produce inflammatory chemicals in the gut that seep into the bloodstream and damage mitochondria, contributing to disease pathogenesis not only in PD but many neurological and metabolic disorders, including obesity, type-2 diabetes, and Alzheimer’s.

The evidence that gut dysbiosis can foster the development of PD raises the possibility that those with the disease could benefit by manipulating their intestinal bacteria and improving their microbiome. Enhancing one’s diet with fermented foods and probiotic supplements may improve gut health and relieve constipation, while also reducing anxiety, depression and memory problems that afflict PD patients.

Cannabis therapeutics may also help to manage PD symptoms and slow the progression of the disease. Acclaimed neurologist Sir William Gowers was the first to mention cannabis as a treatment for tremors in 1888. In his Manual of Diseases of the Nervous System, Grower noted that oral consumption of an “Indian hemp” extract quieted tremors temporarily, and after a year of chronic use the patient’s tremors nearly ceased.

Modern scientific research supports the notion that cannabis could be beneficial in reducing inflammation and assuaging symptoms of PD, as well as mitigating disease progression to a degree. Federally-funded preclinical probes have documented the robust antioxidant and neuroprotective properties of CBD and THCwith “particular application … in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.” Published in 1998, these findings formed the basis of a U.S.government patent on cannabinoids as antioxidants and neuroprotectants.

Pot for Parkinson’s

Although clinical studies focusing specifically on the use of plant cannabinoids to treat PD are limited (because of marijuana prohibition) and convey conflicting results, in aggregate they provide insight into how cannabis may aid those with Parkinson’s. Cannabidiol, THC, and especially THCV all showed sufficient therapeutic promise for PD in preclinical studies to warrant further investigation. Additional research might shed light on which plant cannabinoids, or combination thereof, is most appropriate for different stages of Parkinson’s.

Anecdotal accounts from PD patients using artisanal cannabis preparations indicate that cannabinoid acids (present in unheated whole plant cannabis products) may reduce PD tremor and other motor symptoms. Raw cannabinoid acids (such as CBDA and THCA) are the chemical precursors to neutral, “activated” cannabinoids (CBD, THC). Cannabinoid acids become neutral cannabinoid compounds through a process called decarboxylation, where they lose their carboxyl group through aging or heat. Minimal research has focused on cannabinoid acids, but the evidence thus far suggests that THCA and CBDA have powerful therapeutic attributes, including anti-inflammatory, anti-nausea, anti-cancer, and anti-seizure properties. In a 2004 survey of cannabis use among patients at the Prague Movement Disorder Centre in the Czech Republic, 45 percent of respondents reported improvement in PD motor symptoms.

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Cannabis clinicians are finding that dosage regimens for medical marijuana patients with PDdon’t conform to a one-size-fits-all approach. In her book Cannabis Revealed (2016), Dr. Bonni Goldstein discussed how varied a PD patient’s response to cannabis and cannabis therapeutics can be:

“A number of my patients with PD have reported the benefits of using different methods of delivery and different cannabinoid profiles. Some patients have found relief of tremors with inhaled THC and other have not. A few patients have found relief with high doses of CBD-rich cannabis taken sublingually. Some patients are using a combination of CBD and THC … Trial and error is needed to find what cannabinoid profile and method will work best. Starting a low-dose and titrating up is recommended, particularly with THC-rich cannabis. Unfortunately, THCV-rich varieties are not readily available.”

Juan Sanchez-Ramos M.D., PhD, a leader in the field of movement disorders and the Medical Director for the Parkinson Research Foundation, told Project CBD that he encourages his patients to begin with a 1:1 THC:CBD ratio product if they can get it. In a book chapter on “Cannabinoids for the Treatment of Movement Disorders,” he and coauthor Briony Catlow, PhD, describe the dosage protocol used for various research studies that provided statistically positive results and a dosing baseline for PD. This data was included in a summary of dosing regimens from various studies compiled by Dr. Ethan Russo:

  • 300 mg/day of CBD significantly improved quality of life but had no positive effect on the Unified Parkinson Disease Rating Scale. (Lotan I, 2014)
  • 0.5 g of smoked cannabis resulted in significant improvement in tremor and bradykinesia as well as sleep. (Venderová K, 2004)
  • 150 mg of CBD oil titrated up over four weeks resulted in decreased psychotic symptoms. (Chagas MH, 2014)
  • 75-300 mg of oral CBD improved REM-behavior sleep disorder. (Zuardi AW, 2009)

A threshold dose

Of course, each patient is different, and cannabis therapeutics is personalized medicine. Generally speaking, an optimal therapeutic combination will include a synergistic mix of varying amounts of CBD and THC – although PD patients with sleep disturbances may benefit from a higher THC ratio at night.

Dr. Russo offers cogent advice for patients with PD and other chronic conditions who are considering cannabis therapy. “In general,” he suggests, “2.5 mg of THC is a threshold dose for most patients without prior tolerance to its effects, while 5 mg is a dose that may be clinically effective at a single administration and is generally acceptable, and 10 mg is a prominent dose, that may be too high for naïve and even some experienced subjects. These figures may be revised upward slightly if the preparation contains significant CBD content … It is always advisable to start at a very low dose and titrate upwards slowly.”

For information about nutritional supplementation to help manage PD, visit the Life Extension Foundation Parkinson’s page.

Lifestyle Modifications for PD Patients

It is important to treat the patient as a whole – mind, body and soul. The following are a few lifestyle modifications that may provide relief from PD symptoms and improve quality of life.

  • Do cardio aerobic exercise: This benefits the body in so many ways, including stimulating the production of one’s endocannabinoids, increasing oxygen in the blood supply, mitigating the negative impact of oxidative stress, and boosting the production of BDNF, a brain-protecting chemical found to be low in PD patients.
  • Eat more fruits and vegetables: The old saying “garbage in, garbage out” is so true. The majority of PDpatients suffer from chronic constipation. A high fiber diet can be helpful in improving gut motility and facilitating daily bowel movements.
  • Get restful sleep: Not getting good sleep can undermine one’s immune function, cognition and quality of life. The importance of adequate restful sleep cannot be over emphasized.
  • Reduce protein intake – This may help reduce the accumulation of protein bodies that result in Lewy bodies that appear in the enteric nervous system and the central nervous system and increase the uptake of L-dopa.
  • Practice meditation, yoga or Tai Chi: The focus on the integration of movement and breath not only improve mobility but it also improves cognition and immunity. One study showed an increase in grey matter density in the areas of the brain associated with PD. Another showed that yoga improved balance, flexibility, posture and gait in PD patients. Research shows that tai chi can improve balance, gait, functional mobility, and overall well being.
  • Consume probiotic food and supplements: Probiotic foods — raw garlic, raw onions, bananas, asparagus, yams, sauerkraut, etc.— are a great source for the good bacteria in your large intestine. Augmenting your diet with probiotic supplements, especially after taking antibiotics, can support the immune system by helping to repopulate the upper digestive tract with beneficial bacteria. Consult your doctor regarding a recommendation for a quality probiotic.
  • Drink coffee: The risk of PD is considerably lower for men who consume coffee daily.

Nishi Whiteley, a Project CBD research associate and contributing writer, is the author of Chronic Relief: A Guide to Cannabis for the Terminally and Chronically Ill (2016). Special thanks to Juan Sanchez-Ramos for reviewing this article, Ethan B. Russo, M.D. for providing a summary of Parkinson’s research for inclusion in this article, and to Adrian Devitt-Lee for his research support.

Copyright, Project CBD. May not be reprinted without permission.


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(1) An inverse agonist binds directly to a receptor and modifies it in a way that causes the receptor to have the opposite effects of activating it normally.

(2) MPTP was found in an underground meperidine (Demerol) synthesis that caused a small epidemic of Parkinson syndrome in i.v. drug abusers in the San Francisco area in the mid-1980s.

The presence of Lewy bodies (a-synuclein protein clusters) in other parts of the body could potentially serve as an early detection marker for PD, especially in the olfactory bulb and the enteric nervous system.

(4) Peres-Prado et al analyzed gut microbiota in PD patients compared to controls and found the following:

  • Prevotellaceae, a bacterium which supports the production of health-promoting short chain fatty acids (SCFA), biosynthesis of thiamine and folate, and is thought to be associated with increased gut permeability, was 78% lower in the feces of PD patients versus that of their sex-matched and age-matched controls.
  • Biopsies of colonic tissue retrieved from PD patients indicate high levels of tumor necrosis factor-alpha and other inflammatory agents.
  • A lower abundance of SCFA-producing and anti-inflammatory bacteria from the class of Blautia, Coprococcus, and Roseburia were found in fecal samples of PD patients. (Paula Perez-Pardo, 2017)
  • Gastric abnormalities may increase small intestinal bacterial overgrowth (SIBO). SIBO is prevalent in PD patients and correlates directly to worse motor dysfunction.
  • Gut-derived lipopolysaccharide (LPS – an inflammatory toxin produce by bacteria) promotes the disruption of the blood-brain barrier.
  • Impaired gherlin, a gut hormone known as the hunger hormone, is thought to be associated with maintenance and protection of dopamine function in the nigrostriatal pathway which is one of four major dopamine pathways and is particularly involved in movement. Impaired gherlin has been reported in PD patients.

CBD & DRUG INTERACTIONS

CBD-DRUG INTERACTIONS: ROLE OF CYTOCHROME P450

At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds.
BY ADRIAN DEVITT-LEE ON SEPTEMBER 08, 2015
With cannabidiol (CBD) poised to become widely available in pharmaceutical, nutraceutical, and herbal preparations, medical scientists are taking a closer look at CBD-drug interactions.
CBD cannabis drug interactions
Photo credit: Scientific Images

Cannabidiol is a safe, non-intoxicating, and non-addictive cannabis compound with significant therapeutic attributes, but CBD-drug interactions may be problematic in some cases.

CBD and other plant cannabinoids can potentially interact with many pharmaceuticals by inhibiting the activity of cytochrome P450, a family of liver enzymes. This key enzyme group metabolizes most of the drugs we consume, including more than 60 percent of marketed meds.

At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds, including tetrahydrocannabinol (THC), which causes the high that cannabis is famous for.

Metabolizing THC

When THC or any other foreign compound enters the body, it is metabolized. This process is generally very complicated. Metabolizing something properly can involve multiple molecular pathways and various enzymes that enable the body to get rid of the compound (often done by adding something to the original compound). Or metabolism can entail breaking down a compound into a more basic molecule that the body then uses.

Products of a drug’s metabolism are called its metabolites. These metabolites can have very different properties than the initial drug. Ethanol, for example, owes some of its effects, including much of the hangover, to its two-step metabolism. The buildup of acetaldehyde in the liver—while ethanol is converted first to acetaldehyde and then to acetic acid—is a major reason for ethanol’s liver toxicity and the nausea and vomiting caused by excessive consumption.

THC metabolites contribute significantly to the effects of cannabis consumption. Eleven-hydroxy-THC (11-OHTHC), for example, is a THC metabolite that activates the CB1 cannabinoid receptor in the brain and induces a high more potently than THC itself. This means that the body’s metabolism of THC can make it more potent.

Cytochrome P450 enzymes contribute to the metabolism of drugs by oxidizing them, which generally means incorporating an oxygen atom into the drug’s molecular structure. Oxidation will usually make a compound more water soluble and therefore easier for the kidneys to filter out. Both steps in the metabolism of ethanol, mentioned above, and the conversion of THC into 11-OHTHC involve oxidation (though ethanol is not oxidized specifically by cytochrome P450).

Different routes of cannabinoid administration have different effects. Inhaled THC enters capillaries in the lungs, passes into general circulation through the pulmonary arteries, and quickly crosses the blood-brain barrier. When ingested orally, however, THC is absorbed in the small intestine and then carried to the liver, where it is metabolized by subclasses of cytochrome P450 (abbreviated CYP), specifically the CYP2C and CYP3A enzymes.

These liver enzymes also metabolize CBD, converting it into 7-OHCBD and 6-OHCBD. But there has been relatively little research into the properties of these CBD metabolites.

Metabolizing CBD

The way CBD interacts with cytochrome P450 is pivotal; in essence, they deactivate each other. Preclinical research shows that CBD is metabolized by cytochrome P450 enzymes while functioning as a “competitive inhibitor” of the same liver enzymes. By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents cytochrome P450 from metabolizing other compounds.

The extent to which cannabidiol behaves as a competitive inhibitor of cytochrome P450 depends on how tightly CBD binds to the active site of the metabolic enzyme before and after oxidation. This can change greatly, depending on how—and how much—CBD is administered, the unique attributes of the individual taking this medication, and whether isolated CBD or a whole plant remedy is used.

If the dosage of cannabidiol is low enough, it will have no noticeable effect on CYP activity, but CBD may still exert other effects. There is no clearly established cut-off dose, below which CBD does not interact with other drugs. A 2013 report on a clinical trial using GW Pharmaceutical’s Sativex, a whole plant CBD-rich sublingual spray, found no interactions with CYP enzymes when approximately 40mg of CBD were administered. A subsequent clinical trial, however, found that 25mg of orally administered CBDsignificantly blocked the metabolism of an anti-epileptic drug.

How do CBD-generated changes in cytochrome P450 activity impact the metabolic breakdown of THC? Animal studies indicate that CBD pretreatment increases brain levels of THC. That’s because CBD, functioning as a competitive inhibitor of cytochrome P450, slows down the conversion of THC into its more potent metabolite, 11-OHTHC. Consequently, THC remains active for a longer duration, but the peak of the extended buzz is blunted somewhat under the influence of cannabidiol.

Other factors figure prominently in CBD’s ability to lessen or neutralize the THC high.

Grapefruit and Ganja

Lester Bornheim, a research pharmacologist at the University of California in San Francisco, was among the first scientists to study the metabolism of CBD. In 1987, he was awarded a NIDA grant to investigate the effects of phytocannabinoids on cytochrome P450 enzymes. THC and cannabinol (CBN) also inhibit CYPactivity, but CBD, of all the plant cannabinoids studied, is the strongest cytochrome P450 deactivator.

“It’s a very unusual enzyme. Almost all other enzymes are designed to fit a single substrate and carry out a single chemical process resulting in a single product,” Bornheim noted, whereas numerous drugs are substrates for cytochrome P450, which seems to function like a generic breakdown mechanism for a wide range of exogenous and endogenous substances.

In 1999, Bornheim addressed the annual gathering of the International Cannabinoid Research Society (ICRS) and drew attention to the possibility that CBD could interfere with the metabolism of many medications. A year earlier, a team of Canadian scientists identified certain compounds in grapefruit that inhibit the expression of some cytochrome P450 enzymes—which is why physicians often warn patients not to eat grapefruit before taking their meds. CBD, it turns out, is a more potent inhibitor of cytochrome P450 enzymes than the grapefruit compound Bergapten (the strongest of several grapefruit components that inhibit CYPs).

What does this mean in practical terms for a medical marijuana patient on a CBD-rich treatment regimen who takes a prescription blood-thinner like warfarin, for example? CBD reduces the enzymatic degradation of warfarin, thereby increasing its duration of action and effect. A person taking a CBD-rich product should pay close attention to changes in blood levels of warfarin, and adjust dosage accordingly as instructed by their doctor.

Cancer and Epilepsy

In cancer treatment, the precise dosing of chemotherapy is extremely important; doctors often struggle to find the maximum dose that will not be catastrophically toxic. Many chemotherapy agents are oxidized by CYPs before their inactivation or excretion. This means that for patients using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the cytochrome-mediated metabolism of the chemotherapy and dosage adjustments aren’t made, the chemotherapy agent could accumulate within the body to highly toxic levels.

By and large, however, there have been few reported adverse cannabinoid-drug interactions among the many cancer patients who use cannabis to cope with the wrenching side effects of chemotherapy. It is possible that whole plant cannabis, with its rich compensatory synergies, interacts differently than the isolated CBD that is administered in most research settings. As well, the cytoprotective effects of the cannabinoids may mitigate some of the chemotherapeutic toxicity.

Some epileptic patients have encountered issues with how CBD interacts with their anti-seizure medication. A small clinical study at Massachusetts General Hospital involving children with refractory epilepsy found that CBD elevated the plasma levels and increased the long-term blood concentrations of clobazam, an anticonvulsant, and norclobazam, an active metabolite of this medication. A majority of these children needed to have their dose of clobazam reduced due to side effects. Given that both clobazam and CBD are metabolized by cytochrome P450 enzymes, a drug-drug interaction is not surprising. Published in May 2015, the study concluded that “CBD is a safe and effective treatment of refractory epilepsy in patients receiving [clobazam].” But the report also emphasized the importance of monitoring blood levels for clobazam and norclobazam in patients using both CBD and clobazam.

Dr. Bonni Goldstein has observed cases in which small doses of high-CBD/low-THC cannabis oil concentrate seemed to aggravate seizure disorders rather than quell them. How could this happen, given CBD’s renown anti-epileptic properties?

A 1992 review by Lester Bornheim and his colleagues indicated that CBD inhibits some cytochrome P450enzymes at smaller doses than what is required for CBD to exert an anti-epileptic effect. This means that a certain dose of CBD could alter the processing of an anti-epileptic drug taken by the patient, but this amount of CBD might not be enough to provide any anti-epileptic relief itself. The advice some physicians offer in this situation may seem counterintuitive: Increase the dose of CBD—perhaps even add a little more THC (or THCA, the raw, unheated, non-psychoactive version of THC)—and this may be more effective for seizure control.

Enigmatic Enzymes

But why would preventing the breakdown of an anti-epileptic drug reduce its effect? There are a number of possible answers, depending on the drug in question. The active component of the drug (the chemical that exerts an anti-epileptic effect) may be a breakdown product of the actual drug taken. So, by slowing the metabolism of the original drug, CBD would make that drug less active.

Other explanations are conceivable. For example, if the activity of certain CYPs is slowed, the drug may be broken down by another metabolic pathway, the products of which could then interfere with the drug’s activity. Or perhaps the inhibition of CYPs is not the predominant way that CBD interacts with certain anti-epileptic medications.

To complicate matters even further, a presentation by Dr. Kazuhito Watanabe at the 2015 International Cannabinoid Research Society meeting in Nova Scotia disclosed preliminary evidence that cannabidiol may “induce”—meaning amplify the activity of—some cytochrome P450 enzymes. (Induction of a protein involves increasing the transcription of its corresponding mRNA, which leads to greater synthesis of the protein.) This suggests that CBD can either increase or decrease the breakdown of other drugs. Again, it depends on the drug in question and the dosages used.

Any pharmaceutical, nutraceutical or green rush scheme to exploit the therapeutic potential of CBD must reckon with the fact that cannabidiol can both inactivate and enhance various cytochrome P450 enzymes in the liver—and this can potentially impact a wide range of medications. Drug interactions are especially important to consider when using life-saving or sense-saving drugs, drugs with narrow therapeutic windows, or medications with major adverse side effects. In particular, those who utilize high doses of CBDconcentrates and isolates should keep this in mind when mixing remedies.

Adrian Devitt-Lee is a senior at Tufts University, studying mathematics and chemistry.

Learn More:

AED Potential Interactions with CBD

Copyright, Project CBD. May not be reprinted without permission.

PHARMACEUTICAL INTERACTIONS: WHAT YOU NEED TO KNOW

CANNABINOID-PHARMACEUTICAL INTERACTIONS: WHAT YOU NEED TO KNOW

Drug interactions can be both useful and dangerous. Learn how CBD and THC may inhibit or amplify the effects of pain meds, statins, blood thinners, insulin & more.
BY ADRIAN DEVITT-LEE ON JANUARY 16, 2018
Highlights:
  • THC and CBD interact with many common pharmaceuticals. Cannabinoids can inhibit or potentiate the effects of various drugs
  • More than half of all pharmaceuticals – including THC and CBD – are metabolized by a family of enzymes called cytochrome P450
  • Interactions between cannabinoids and other drugs can be exploited to mitigate side effects while synergistically improving a patient’s quality of life
  • Cannabinoid-opioid interactions show great therapeutic potential. THC significantly enhances the painkilling effects of opiates, while CBD is most promising for reducing withdrawal and dependence
Cannabis samples being prepared at Sonoma Lab Works for analysis
Cannabis samples being prepared at Sonoma Lab Works

Interactions between medications are very common, especially in elderly populations that medicate for pain, diabetes and high cholesterol. The geriatric population is also the fastest-growing group of medical cannabis users. Cannabis has demonstrated efficacy in treating pain, and some phytocannabinoids have been suggested for various metabolic conditions. Thus it is important to understand how cannabinoids can interact with common pharmaceuticals, both to predict and prevent negative interactions, while taking advantage of situations where cannabis and pharmaceuticals act synergistically.

Drug interactions can be both useful and dangerous. A drug that potentiates an opiate, for example, may increase the painkilling effect, but could also increase the likelihood of overdose. Or a second analgesic could allow the dose of an opiate to be reduced, which would slow tolerance and decrease other side effects.

But understanding all the convergent biological pathways of two drugs is difficult. Examining the metabolic interactions between drugs is one way to generically predict drug interactions: since more than half of all pharmaceuticals are metabolized by a family of enzymes called cytochrome P450 (CYP), knowing how cannabinoids affect CYPs provides a good first approximation to phytocannabinoid-drug interactions. In general, inhibiting the CYPs that metabolize a pharmaceutical will increase its blood concentration, leading to an increase in both effects and toxicity. But for prodrugs—which are metabolized into the active compound—inhibition of metabolism will decrease both the desired and adverse effects. And the interaction can change from inhibition to activation with different drugs. Due to complications like these, it is much easier to predict whether drug interactions are likely than to predict their exact effect.

This review will describe potential cannabinoid-drug interactions in the context of treating pain (with opiates and non-steroidal anti-inflammatory drugs) and metabolic disorders (using insulin, warfarin and statins). Owing to the highly complicated role of cannabinoids in the cardiovascular system—with at least four cannabinoid-like receptors initiating changes in the vasculature, multiple phases to the effects, and opposing effects under normal, stressed and pathological conditions–cannabinoid interactions with drugs used to treat hypertension are beyond the scope of this article …

You can read the full article by downloading the PDF attached below, or by viewing it in the Fall Edition of Sonoma Medicine magazine where this article was originally published.

Endocanabinoid Deficiency Leads to Fibromyalgia. National Pain Foundation Survey

In 2014, a survey of more than 1,300 fibromyalgia patients by the National Pain Foundation and National Pain Report found medical marijuana is more effective than Lyrica, Cymbalta or Savella, the three drugs approved by the Food and Drug Administration to treat the disorder. (If you’re curious about the effectiveness of Lyrica, Cymbalta and Savella, then you might be interested in my post, “Why your fibro meds aren’t working.”)

There’s growing anecdotal evidence that marijuana relieves fibromyalgia pain, but actual research is still scant. Cannabis remains a schedule I controlled substance in the United States, making it difficult for researchers to study the plant’s pain-relieving properties. To date, there have been less than a handful of small studies using cannabis or its derivatives to treat fibromyalgia. Most of those have shown it to be beneficial, especially for pain relief.

But why does cannabis seem to work so well? Dr. Ethan Russo, medical director of PHYTECS, believes fibromyalgia’s multifaceted symptoms may be caused by a deficiency in the body’s endocannabinoid system (ECS), a condition he calls Clinical Endocannabinoid Deficiency (CED). Maybe the reason cannabis is so effective is because it’s simply supplementing what the body needs – similar to how people take a supplement to treat vitamin D or B12 deficiency.

Russo explores the evidence behind his hypothesis in a soon-to-be published review entitled, “Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel and other Treatment-Resistant Syndromes.” While his idea is still theoretical, there is some early research indicating he may be onto something.

The ECS is made up of cannabinoid receptors within the brain, spinal cord, nerves, gut, organs and other locations in the body. It helps the body maintain homeostasis and is involved in a number of physiological processes, including pain sensation, mood, memory and appetite, among others. The body naturally makes endocannabinoids – the same kinds of endocannabinoids found in cannabis – that feed the ECS and keep it functioning.

Fibromyalgia causes symptoms throughout the body, with the primary ones being pain, fatigue, cognitive and sleep difficulties. Certain conditions, like irritable bowel syndrome (IBS) and migraine, are extremely common among those with fibromyalgia – so much so that Russo believes they may all be connected to an ECS deficiency.

His theory makes sense. The ECS plays a role in so many of the body’s major systems, so if it was indeed malfunctioning, that would account for why fibro sufferers have such varied symptoms. Supplementing the ECS with cannabinoids from the cannabis plant would, in theory, relieve symptoms because the deficiency is being treated.

Russo first posited that fibromyalgia, IBS and migraine may be caused by an ECS deficiency back in 2001. (Click here to read his first review on the subject.) His latest review gives an update on new research that supports ECS deficiency as a possible culprit for fibromyalgia, IBS and migraine.

“Additional studies have provided a firmer foundation for the theory,” he writes in the review, “while clinical data have also produced evidence for decreased pain, improved sleep and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the endocannabinoid system.”

CED is based on the premise that many brain disorders have been linked to neurotransmitter deficiencies. For example, dopamine has been implicated in Parkinson’s disease, and serotonin and norepinephrine have been associated with depression.

“If endocannabinoid function were decreased, it follows that a lowered pain threshold would be operative, along with derangements of digestion, mood and sleep among the almost universal physiological systems sub-served by the ECS,” Russo writes.

That’s a mouthful, but essentially it means if the ECS isn’t properly working, then it could account for the pain, sleep, digestive and other issues so common among fibromyalgia patients. Adding cannabinoids to the body through the use of cannabis may help to bring the ECS back into balance.

“It’s a key in a lock in your body that exists for a reason,” explains Dr. Jahan Marcu, chief scientist with Americans for Safe Access. “We send in cannabinoids to activate this system that’s supposed to be working. It’s a sort of care and feeding of the ECS so it can do its job.”

The best evidence for CED comes from an Italian migraine study, which found reduced levels of an endocannabinoid known as anandamide in patients with chronic migraines versus healthy controls.

“Reduced [anandamide] levels in the cerebrospinal fluid of chronic migraine patients support the hypothesis of the failure of this endogenous cannabinoid system in chronic migraine,” read the study.

Unfortunately, the Italian study will probably never be repeated in the United States because it required risky and invasive lumbar punctures.

In the gut, the ECS modulates the movement of food along the digestive tract, the release of digestive juices to break down food and inflammation.

Cannabis has long been used to treat digestive issues and was one of the first effective treatments for diarrhea caused by cholera in the 19th century.

“Unfortunately while many patient surveys have touted the benefit of cannabinoid treatment of IBS symptoms, and abundant anecdotal support is evident on the Internet, little actual clinical work has been accomplished,” Russo writes.

A few studies using marijuana for fibromyalgia have had positive results. Overall, marijuana has been found to decrease pain and anxiety, and improve sleep and general well-being.

“There is actually some evidence that the levels of at least one endocannabinoid (anandamide) increase in the circulation of patients with fibromyalgia,” says Prof. Roger G. Pertwee from the University of Aberdeen in Scotland. “There is also considerable evidence that anandamide is often released in a manner that reduces unwanted symptoms such as pain and spasticity in certain disorders. … It is generally accepted that THC, the main psychoactive constituent of cannabis, can relieve pain, including neuropathic pain for example, by directly activating cannabinoid receptors. … Some non-psychoactive constituents of cannabis have also been found to relieve signs of pain, at least in animal models.”

For anecdotal evidence, Russo cites the National Pain Foundation/National Pain Report survey in his review, saying, “The results of the survey strongly favor cannabis over the poorly effective prescription medicines. These results certainly support an urgent need for more definitive randomized controlled trials of a well-formulated and standardized cannabis-based medicine in fibromyalgia inasmuch as existing medicines with regulatory approval seem to fall quite short of the mark.”

More research needs to be done to either prove or disprove CED’s existence.

“What we really need is randomized controlled trials to look at this more carefully, and that’s the only kind of evidence that the [Food and Drug Administration] and most doctors are going to find acceptable in the end,” Russo says.

MRI and PET scans are not yet able to detect endocannabinoid levels in living patients, but as technology advances, that may become a possibility. The ability to actually test endocannabinoid levels in fibromyalgia patients and compare those against healthy controls would help to confirm Russo’s theory.

“We’re on the edge of having that capability,” Russo says. “It’s in my plans to look at this type of thing in the future.”

Source: https://fedupwithfatigue.com

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